In recent years, the bis-tetrahydrofuranyl ligand has become an important ligand in the design of HIV-protease inhibitors. Since its discovery, it has been the salient feature in many drug candidates. Darunavir, (1), the first FDA approved second generation protease inhibitor, is currently being used in the treatment of naïve and drug resistant HIV. Since its approval, Brecanavir, (2) and GSK-8374, (3) have also capitalized on this moiety.

There have been several syntheses for the bis-THF ligand (a. Ghosh, A. K.; et al.; Tetrahedron Letters, 1995, 36, 505-508. (b) Doan, B. D.; et al.; WO 03/024974 A2. (c) A. K. Ghosh et al. Tetrahedron Letters, 1999, 40, 1083-1086. (d) Lemaire, S. F. E.; et al.; WO/2008/055970; the disclosure of each of the foregoing publications, and each additional publication cited herein, is incorporated herein in its entirety by reference. A method utilizing a photochemical irradiation with 1,3-dioxolane to give the key intermediate in good diastereomeric ratios has been reported (Ghosh, A. K., et al., M. J. Org. Chem. 2004, 69, 7822-7829). Use of an asymmetric anti-aldol condensation to obtain the key intermediate needed to obtain the bis-THF ligand has also been described (Ghosh, A. K., et al., Synthesis, 2006, 3015-3018). Two chiral syntheses have been reported, both of which include a conjugate addition of nitromethane (Quaedflieg, P. J. L. M., et al., Org. Lett. 2005, 7, 5917-5920). Other syntheses have been attempted with the use of various catalysts to obtain the desired product (Black, D. M., et al., Tetrahedron: Asymmetry, 2008, 19, 2015-2019). However, many of the previously disclosed methods require late-stage resolution to obtain the enantiomerically pure ligand. Accordingly, alternative processes for preparing this important ligand in second generation protease inhibitors in the treatment of HIV are useful.